Repository logo

Structural basis for a complex I mutation that blocks pathological ROS production.

Published version

Change log



Mitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia-reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the "deactive" state, usually formed only after prolonged inactivity. Despite its tendency to adopt the "deactive" state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.



Amino Acid Substitution, Animals, Cryoelectron Microscopy, DNA, Mitochondrial, Disease Models, Animal, Disease Resistance, Electron Transport, Electron Transport Complex I, Humans, Isolated Heart Preparation, Leucine, Male, Mice, Mice, Transgenic, Mitochondria, Mitochondrial Membranes, Myocardial Reperfusion Injury, NAD, NADH Dehydrogenase, Oxidation-Reduction, Point Mutation, Proline, Reactive Oxygen Species

Journal Title

Nat Commun

Conference Name

Journal ISSN


Volume Title



Springer Science and Business Media LLC
Wellcome Trust (202905/Z/16/Z)
Medical Research Council (MR/P000320/1)
Wellcome Trust (206171/Z/17/Z)
Medical Research Council (MC_U105663141)
Medical Research Council (MC_U105663142)
Medical Research Council (MC_UU_00015/7)
Wellcome Trust (110159/Z/15/Z)
Medical Research Council (MC_UU_00015/8)
MRC (MC_UU_00015/2)
Medical Research Council (MC_UU_00015/3)
MRC (MC_UU_00015/8)